PROJECT SUMMARY/ABSTRACT - Reduced Endothelial Function, Brain, and Cognition Subclinical cardiovascular diseases (CVD), pre-cursors to CVD that occur without overt symptoms, are associated with subtle cognitive decrements that often presage stroke and dementia. Reduced endothelial function is a subclinical CVD with unique prognostic value for cardiovascular events and pathophysiologic importance in the development of hypertension and atherosclerosis, known risk factors for stroke and dementia. Despite the prognostic value of reduced endothelial function, few studies have investigated its relation to cognitive function and none have sampled older adults free of clinical disease. Potential brain mechanisms responsible for reduced endothelial function and cognitive function relations among individuals with CVD and stroke include reduced cerebral blood flow and white matter hyperintensities. These are likely attributed to compromised endothelium integrity and inhibition of nitric oxide synthase. However, among older adults without clinical disease, underlying brain pathology is unknown. Furthermore, brain abnormalities and related cognitive outcomes may be more severe among African Americans who are most vulnerable to cognitive decline and dementia due to high rates of CVD, impaired vascular function, and psychosocial risk factors. We propose that reduced endothelial function may have utility as a screening tool for cognitive decrements, and because it is highly amenable to intervention, may represent a reversible risk factor for cognitive decline and dementia. Our central hypothesis is that reduced endothelial function will be associated with poorer cognitive function, after controlling for standard adjustment variables, carotid atherosclerosis, and arterial stiffness, and that MRI-assessed brain abnormalities will serve as underlying mediators. Additionally, we hypothesize that associations will be more strongly pronounced among African Americans. In this COBRE subproject, older adults will complete an eligibility screening and three study visits. Brachial artery flow- mediated dilation will be used to assess endothelial function. A neuropsychology battery will be administered to assess cognitive performance in the domains of attention and executive function, learning and memory, and perceptuo-motor speed. Cranial MRI will be acquired using a 1.5T magnet to assess total and prefrontal gray matter volumes and total and prefrontal white matter lesion volumes and explore unique patterns of association. We expect to demonstrate that reduced endothelial function is associated with poorer cognitive performance and that several brain abnormalities mediate these associations. We also expect associations to be more pronounced among African Americans. This project will be the first to investigate the influence of reduced endothelial function on cognitive function among older adults without clinical disease, include MRI to investigate underlying brain pathology, and include a racially diverse sample. Data collected from this subproject would allow for further exploration of these aims through an R01 including the potential of conducting a longitudinal study.